The goal of this project is to improve means to prevent and treat chronic graft-versus-host disease (GVHD) which is the major determinant of late nonrelapse mortality following allogeneic stem cell transplantation. Currently 1,029 individuals survive 5 to 25 years after allogeneic transplantation at this Center. Among a cohort of 443 patients with chronic myelogenous leukemia in chronic phase transplanted since 1987 from HLA-identical sibling (n=251) or mismatched/unrelated (n=192) donors, late complications included: chronic GVHD (n=257), bacteremia (n=142 episodes), cataracts (n=119), lung disease (n=59), bone disease (n=50), and secondary neoplasms (n=10). Multivariate analysis confirmed a highly significant association of all infections developing after day 120 with chronic GVHD. Use of alternative donor marrow and use of corticosteroids before onset of chronic GVHD were also significant independent covariates. Accordingly, we propose four interrelated specific aims to improve morbidity-free survival: 1) Provide comprehensive follow-up to identify evolving late effects of transplant regimens; 2) Evaluate means to prevent chronic GVHD and steroid toxicity by prolonging the duration of cyclosporine (CSP) prophylaxis or by use of a novel regimen of CSP/rapamycin immunosuppression; 3) Improve treatment of chronic GVHD by selecting thalidomide, FK506, rapamycin, or mycophenolate mofetil from pilot studies for study in Phase III trials; 4) Evaluate new diagnostic and interventive methods to reduce other causes of posttransplant morbidity (e.g. cataract formation and bone disease) and determine in a placebo- controlled study of immunoglobulin prophylaxis whether infections and mortality can be reduced after unrelated donor transplantation. This project is the clinical hub providing continuous monitoring of a large number of transplant recipients for real time investigation of abnormalities of hematopoietic function, graft rejection and GVHD. Although long-term survival has improved in recent years, clinical study of chronic GVHD and late events is vital for further improvement in patient outcome.